1. Field of the Invention
The present invention relates to novel compounds which are inhibitors of receptor tyrosine kinases of the AXL receptor family. These compounds are suitable for the treatment or prevention of disorders associated with, accompanied by or caused by hyperfunction of a receptor of the AXL family. The compounds are suitable for the treatment of hyperproliferative disorders, such as cancer, particularly cancer metastases.
2. Description of the Relevant Art
Breast cancer is the most common malignant disease in western women. In these patients, it is not the primary tumour, but its metastases at distant sites that are the main cause of death (1). Despite surgical removal of the primary tumour, relapse at local or distant sites may occur because of incomplete removal of primary tumour tissue or the presence of micrometastases undetectable at the time of diagnosis. The development of chemotherapy as well as endocrine- and radiation therapy, administered as adjuvant treatment after surgery, has led to a reduction in the risk of relapse to 20-40%. However, adjuvant treatment has a wide range of acute and long-term side effects. Over the past twenty years, with the advances in understanding the molecular basis of signalling pathway dysregulation in various cancers, a new era of cancer therapy has begun, which is characterized by the identification of critical regulators of malignant properties of cancer cells as molecular targets (2, 3).
Deregulated expression of protein kinases by gene deletion, -mutation or -amplification has been found to be important for tumour initiation and -progression, involving cancer cell proliferation, -survival, -motility and -invasivity as well as tumour angiogenesis and chemotherapy resistance (4, 5). Because of the advanced understanding of their critical functions in    oncogenesis, protein kinases have been at the forefront of targeted cancer therapy development since the 1980s. Most of the novel targeted cancer therapeutics currently approved by the FDA in clinical use is interfering with the signalling action of protein kinases. More than 100 additional protein kinase inhibitors and antibodies are in clinical trials, making kinases after G protein-coupled receptors the second most popular drug target class in the pharmaceutical and biotech industries (3).
In breast cancer, the receptor tyrosine kinase HER2/neu is overexpressed due to gene amplification in tumours of about 25% of breast cancer patients, and enhanced expression correlates with lack of response to adjuvant therapy and poor prognosis (6). Based on this discovery, Herceptin, a monoclonal antibody against HER2/neu oncoprotein, has been developed and is in clinical use since 1998 both as a single agent and in combination with chemotherapies for HER2/neu overexpressing metastatic breast cancer, which has helped to significantly prolong survival of patients (7, 8). However, metastatic breast cancer patients showing no overexpression of HER2/neu do not benefit from this therapy. Therefore, novel therapeutic targets are still urgently needed for intervention in breast cancer metastatic progression.
To identify the genes that mediate progression of breast cancer, we have focused on key elements of the phosphoprotein-mediated signalling system because of its established role in human cancer. After systematically analyzing expression profiles of kinases of thirteen weakly invasive and eight highly invasive breast cancer cell lines and normal mammary epithelia cell lines by cDNA array hybridization analysis, we identified a cluster of genes characteristic for highly invasive cell types. The RTK AXL was part of the gene cluster predictive of the aggressiveness of breast cancer cells.
The mammalian AXL RTK subfamily includes three closely related members: AXL, SKY, and MER. The subfamily is characterised by an extracellular domain, consisting of two immunoglobulin-like domains followed by two fibronectin type 3-like domains. GAS6, originally isolated as a growth arrest-specific    gene, is the common ligand for AXL subfamily receptors (9-11). GAS6 has the highest affinity for AXL, followed by SKY, and finally MER (11). GAS6-AXL signalling has been implicated in a host of discrete cellular responses including cell survival, proliferation, migration and adhesion (12).
AXL was originally isolated from patients with chronic myelogenous leukaemia and was shown to have transforming potential when overexpressed (13, 14). Subsequently, AXL expression has been reported in a wide variety of human cancers (15-20). Especially, in breast cancer patients a significant correlation was found between AXL and tumour stage (15). Moreover, some reports indicated that AXL might be involved in cancer progression (21, 22).   